RU2606501C2 - Производные с-арилглюкозидов, способ их получения и фармацевтическое применение - Google Patents

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Publication number

RU2606501C2

RU2606501C2 RU2013107748A RU2013107748A RU2606501C2 RU 2606501 C2 RU2606501 C2 RU 2606501C2 RU 2013107748 A RU2013107748 A RU 2013107748A RU 2013107748 A RU2013107748 A RU 2013107748A RU 2606501 C2 RU2606501 C2 RU 2606501C2

Authority

RU

Russia

Prior art keywords

phenyl

chloro

methyl

mmol

methoxy

Prior art date

2010-08-10

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• 238000002360 preparation method Methods 0.000 title claims abstract description 5
• 229930182478 glucoside Natural products 0.000 title 1
• 150000001875 compounds Chemical class 0.000 claims abstract description 214
• 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims abstract description 84
• 229910052736 halogen Inorganic materials 0.000 claims abstract description 46
• 150000002367 halogens Chemical class 0.000 claims abstract description 46
• 150000003839 salts Chemical class 0.000 claims abstract description 37
• 229910052805 deuterium Inorganic materials 0.000 claims abstract description 20
• 125000002887 hydroxy group Chemical group [H]O* 0.000 claims abstract description 20
• YZCKVEUIGOORGS-OUBTZVSYSA-N Deuterium Chemical compound [2H] YZCKVEUIGOORGS-OUBTZVSYSA-N 0.000 claims abstract description 19
• 125000000000 cycloalkoxy group Chemical group 0.000 claims abstract description 18
• 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 18
• 239000001257 hydrogen Substances 0.000 claims abstract description 18
• 238000000034 method Methods 0.000 claims abstract description 16
• 238000006243 chemical reaction Methods 0.000 claims abstract description 14
• 239000003814 drug Substances 0.000 claims abstract description 11
• 125000001544 thienyl group Chemical group 0.000 claims abstract description 11
• UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims abstract description 10
• 239000003112 inhibitor Substances 0.000 claims abstract description 9
• 150000002431 hydrogen Chemical class 0.000 claims abstract description 7
• 230000001419 dependent effect Effects 0.000 claims abstract description 6
• 230000000694 effects Effects 0.000 claims abstract description 5
• 125000005843 halogen group Chemical group 0.000 claims abstract description 4
• 125000000217 alkyl group Chemical group 0.000 claims description 77
• PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 claims description 27
• 125000003545 alkoxy group Chemical group 0.000 claims description 26
• 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 18
• 201000010099 disease Diseases 0.000 claims description 17
• 206010012601 diabetes mellitus Diseases 0.000 claims description 14
• 239000008194 pharmaceutical composition Substances 0.000 claims description 12
• 239000011734 sodium Substances 0.000 claims description 12
• DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 claims description 11
• 206010022489 Insulin Resistance Diseases 0.000 claims description 11
• 229910052708 sodium Inorganic materials 0.000 claims description 11
• 208000001072 type 2 diabetes mellitus Diseases 0.000 claims description 11
• 108091052347 Glucose transporter family Proteins 0.000 claims description 10
• 206010060378 Hyperinsulinaemia Diseases 0.000 claims description 10
• 208000008589 Obesity Diseases 0.000 claims description 10
• 208000017442 Retinal disease Diseases 0.000 claims description 10
• 206010038923 Retinopathy Diseases 0.000 claims description 10
• 201000001421 hyperglycemia Diseases 0.000 claims description 10
• 230000003451 hyperinsulinaemic effect Effects 0.000 claims description 10
• 201000008980 hyperinsulinism Diseases 0.000 claims description 10
• 208000017169 kidney disease Diseases 0.000 claims description 10
• 201000001119 neuropathy Diseases 0.000 claims description 10
• 230000007823 neuropathy Effects 0.000 claims description 10
• 235000020824 obesity Nutrition 0.000 claims description 10
• 208000033808 peripheral neuropathy Diseases 0.000 claims description 10
• 208000011580 syndromic disease Diseases 0.000 claims description 10
• 208000002249 Diabetes Complications Diseases 0.000 claims description 9
• 208000031226 Hyperlipidaemia Diseases 0.000 claims description 9
• 235000014113 dietary fatty acids Nutrition 0.000 claims description 9
• 239000000194 fatty acid Substances 0.000 claims description 9
• 229930195729 fatty acid Natural products 0.000 claims description 9
• 150000004665 fatty acids Chemical class 0.000 claims description 9
• 208000006575 hypertriglyceridemia Diseases 0.000 claims description 9
• 238000011282 treatment Methods 0.000 claims description 9
• 206010012655 Diabetic complications Diseases 0.000 claims description 8
• 206010020772 Hypertension Diseases 0.000 claims description 8
• 238000011161 development Methods 0.000 claims description 8
• 201000001320 Atherosclerosis Diseases 0.000 claims description 7
• 102000018711 Facilitative Glucose Transport Proteins Human genes 0.000 claims description 5
• 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 5
• 239000003937 drug carrier Substances 0.000 claims description 3
• 125000004431 deuterium atom Chemical group 0.000 claims description 2
• 238000010511 deprotection reaction Methods 0.000 claims 1
• 150000001975 deuterium Chemical group 0.000 claims 1
• 229940126601 medicinal product Drugs 0.000 claims 1
• 239000000126 substance Substances 0.000 abstract description 64
• WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 abstract description 18
• 239000008103 glucose Substances 0.000 abstract description 18
• 238000004519 manufacturing process Methods 0.000 abstract description 6
• 102000000070 Sodium-Glucose Transport Proteins Human genes 0.000 abstract description 3
• 108010080361 Sodium-Glucose Transport Proteins Proteins 0.000 abstract description 3
• 125000004169 (C1-C6) alkyl group Chemical group 0.000 abstract 6
• 125000004191 (C1-C6) alkoxy group Chemical group 0.000 abstract 1
• 102000034534 Cotransporters Human genes 0.000 abstract 1
• 108020003264 Cotransporters Proteins 0.000 abstract 1
• 230000001681 protective effect Effects 0.000 abstract 1
• XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 297
• 239000011541 reaction mixture Substances 0.000 description 270
• YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 249
• OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 240
• 230000002829 reductive effect Effects 0.000 description 186
• -1 cyano, hydroxyl Chemical group 0.000 description 111
• 239000000706 filtrate Substances 0.000 description 110
• 239000000243 solution Substances 0.000 description 105
• CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 98
• 239000000284 extract Substances 0.000 description 98
• WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 95
• FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 81
• 238000010898 silica gel chromatography Methods 0.000 description 67
• XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 67
• 125000000753 cycloalkyl group Chemical group 0.000 description 63
• 239000007787 solid Substances 0.000 description 59
• 238000005481 NMR spectroscopy Methods 0.000 description 56
• ZMXDDKWLCZADIW-UHFFFAOYSA-N dimethylformamide Substances CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 50
• 125000003118 aryl group Chemical group 0.000 description 49
• 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 48
• VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 48
• YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 47
• 125000001072 heteroaryl group Chemical group 0.000 description 46
• 239000000203 mixture Substances 0.000 description 46
• ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 45
• VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 44
• 239000008346 aqueous phase Substances 0.000 description 39
• 239000011259 mixed solution Substances 0.000 description 39
• 239000012047 saturated solution Substances 0.000 description 37
• HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 36
• 238000004949 mass spectrometry Methods 0.000 description 34
• 238000000746 purification Methods 0.000 description 34
• CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 33
• 125000005343 heterocyclic alkyl group Chemical group 0.000 description 32
• DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 30
• 125000000623 heterocyclic group Chemical group 0.000 description 29
• IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 28
• VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 26
• CTSLXHKWHWQRSH-UHFFFAOYSA-N oxalyl chloride Chemical compound ClC(=O)C(Cl)=O CTSLXHKWHWQRSH-UHFFFAOYSA-N 0.000 description 24
• 125000003342 alkenyl group Chemical group 0.000 description 23
• 125000000304 alkynyl group Chemical group 0.000 description 23
• JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 22
• RFFLAFLAYFXFSW-UHFFFAOYSA-N 1,2-dichlorobenzene Chemical compound ClC1=CC=CC=C1Cl RFFLAFLAYFXFSW-UHFFFAOYSA-N 0.000 description 20
• 238000010828 elution Methods 0.000 description 19
• AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 18
• UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 18
• 239000011780 sodium chloride Substances 0.000 description 18
• CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical class [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 17
• 239000007788 liquid Substances 0.000 description 17
• WSFSSNUMVMOOMR-UHFFFAOYSA-N Formaldehyde Chemical compound O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 description 15
• YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 15
• 125000004093 cyano group Chemical group *C#N 0.000 description 15
• 125000004432 carbon atom Chemical group C* 0.000 description 14
• 238000003756 stirring Methods 0.000 description 14
• AGEZXYOZHKGVCM-UHFFFAOYSA-N benzyl bromide Chemical compound BrCC1=CC=CC=C1 AGEZXYOZHKGVCM-UHFFFAOYSA-N 0.000 description 13
• 125000002619 bicyclic group Chemical group 0.000 description 13
• 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 13
• 239000012279 sodium borohydride Substances 0.000 description 13
• 229910000033 sodium borohydride Inorganic materials 0.000 description 13
• RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 12
• KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 12
• WETWJCDKMRHUPV-UHFFFAOYSA-N acetyl chloride Chemical compound CC(Cl)=O WETWJCDKMRHUPV-UHFFFAOYSA-N 0.000 description 12
• 239000012346 acetyl chloride Substances 0.000 description 12
• 239000008098 formaldehyde solution Substances 0.000 description 12
• 125000001424 substituent group Chemical group 0.000 description 12
• BCNZYOJHNLTNEZ-UHFFFAOYSA-N tert-butyldimethylsilyl chloride Chemical compound CC(C)(C)[Si](C)(C)Cl BCNZYOJHNLTNEZ-UHFFFAOYSA-N 0.000 description 12
• KZMGYPLQYOPHEL-UHFFFAOYSA-N Boron trifluoride etherate Chemical compound FB(F)F.CCOCC KZMGYPLQYOPHEL-UHFFFAOYSA-N 0.000 description 11
• MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 11
• UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 11
• AQRLNPVMDITEJU-UHFFFAOYSA-N triethylsilane Chemical compound CC[SiH](CC)CC AQRLNPVMDITEJU-UHFFFAOYSA-N 0.000 description 11
• 238000004440 column chromatography Methods 0.000 description 10
• 125000006413 ring segment Chemical group 0.000 description 10
• VNGTZLYNGGLPIZ-WCXIOVBPSA-N (3r,4s,5r,6r)-3,4,5-tris(trimethylsilyloxy)-6-(trimethylsilyloxymethyl)oxan-2-one Chemical compound C[Si](C)(C)OC[C@H]1OC(=O)[C@H](O[Si](C)(C)C)[C@@H](O[Si](C)(C)C)[C@@H]1O[Si](C)(C)C VNGTZLYNGGLPIZ-WCXIOVBPSA-N 0.000 description 9
• 125000003282 alkyl amino group Chemical group 0.000 description 9
• 125000005366 cycloalkylthio group Chemical group 0.000 description 9
• 125000003396 thiol group Chemical class [H]S* 0.000 description 9
• 108091006269 SLC5A2 Proteins 0.000 description 8
• 229940098779 methanesulfonic acid Drugs 0.000 description 8
• 229910052757 nitrogen Inorganic materials 0.000 description 8
• 125000003367 polycyclic group Chemical group 0.000 description 8
• 229910000029 sodium carbonate Inorganic materials 0.000 description 8
• 102000058081 Sodium-Glucose Transporter 2 Human genes 0.000 description 7
• 239000003472 antidiabetic agent Substances 0.000 description 7
• 239000008280 blood Substances 0.000 description 7
• 210000004369 blood Anatomy 0.000 description 7
• 125000005842 heteroatom Chemical group 0.000 description 7
• 229910052760 oxygen Inorganic materials 0.000 description 7
• 239000002904 solvent Substances 0.000 description 7
• 229910052717 sulfur Inorganic materials 0.000 description 7
• 238000012360 testing method Methods 0.000 description 7
• 238000004809 thin layer chromatography Methods 0.000 description 7
• CNRYBNTWPLPRIY-CUUWFGFTSA-N (1s,2s,3s,4r,5s)-5-[4-chloro-3-[(4-ethoxy-2,3-difluorophenyl)methyl]phenyl]-1-(hydroxymethyl)-6,8-dioxabicyclo[3.2.1]octane-2,3,4-triol Chemical compound FC1=C(F)C(OCC)=CC=C1CC1=CC([C@@]23O[C@@](CO)(CO2)[C@@H](O)[C@H](O)[C@H]3O)=CC=C1Cl CNRYBNTWPLPRIY-CUUWFGFTSA-N 0.000 description 6
• LEWYCBRUDUVOLG-UHFFFAOYSA-N 1,1,2,2-tetrafluoro-2-(1,1,2,2,3,3,4,4-octafluoro-4-iodobutoxy)ethanesulfonyl fluoride Chemical compound FC(F)(I)C(F)(F)C(F)(F)C(F)(F)OC(F)(F)C(F)(F)S(F)(=O)=O LEWYCBRUDUVOLG-UHFFFAOYSA-N 0.000 description 6
• WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 6
• RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 6
• KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 6
• 108091006277 SLC5A1 Proteins 0.000 description 6
• 102000058090 Sodium-Glucose Transporter 1 Human genes 0.000 description 6
• 150000001733 carboxylic acid esters Chemical class 0.000 description 6
• 238000004128 high performance liquid chromatography Methods 0.000 description 6
• 125000004029 hydroxymethyl group Chemical group [H]OC([H])([H])* 0.000 description 6
• RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 6
• BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 6
• 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 6
• 102000042092 Glucose transporter family Human genes 0.000 description 5
• 210000004027 cell Anatomy 0.000 description 5
• 150000002430 hydrocarbons Chemical group 0.000 description 5
• 210000003734 kidney Anatomy 0.000 description 5
• 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 5
• 125000002950 monocyclic group Chemical group 0.000 description 5
• 229910000030 sodium bicarbonate Inorganic materials 0.000 description 5
• 235000017557 sodium bicarbonate Nutrition 0.000 description 5
• ILMRJRBKQSSXGY-UHFFFAOYSA-N tert-butyl(dimethyl)silicon Chemical compound C[Si](C)C(C)(C)C ILMRJRBKQSSXGY-UHFFFAOYSA-N 0.000 description 5
• 125000001981 tert-butyldimethylsilyl group Chemical group [H]C([H])([H])[Si]([H])(C([H])([H])[H])[*]C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H] 0.000 description 5
• 125000000876 trifluoromethoxy group Chemical group FC(F)(F)O* 0.000 description 5
• ULTLQRPKEDOYSJ-LUYSREMJSA-N (1r,2r,3s,4s,5s)-5-[4-chloro-3-[(2,3-difluoro-4-methoxyphenyl)methyl]phenyl]-1-(hydroxymethyl)-6,8-dioxabicyclo[3.2.1]octane-2,3,4-triol Chemical compound FC1=C(F)C(OC)=CC=C1CC1=CC([C@@]23O[C@](CO)(CO2)[C@H](O)[C@H](O)[C@@H]3O)=CC=C1Cl ULTLQRPKEDOYSJ-LUYSREMJSA-N 0.000 description 4
• GMWMRLJSWBOCQA-GIDFYXQGSA-N (1s,2s,3s,4r,5s)-5-[3-[[5-(4-fluorophenyl)thiophen-2-yl]methyl]-4-methylphenyl]-1-(hydroxymethyl)-6,8-dioxabicyclo[3.2.1]octane-2,3,4-triol Chemical compound CC1=CC=C([C@@]23O[C@@](CO)(CO2)[C@@H](O)[C@H](O)[C@H]3O)C=C1CC(S1)=CC=C1C1=CC=C(F)C=C1 GMWMRLJSWBOCQA-GIDFYXQGSA-N 0.000 description 4
• CBFXWKNXMYIBMA-CUUWFGFTSA-N (1s,2s,3s,4r,5s)-5-[4-chloro-3-(2,3-dihydro-1-benzofuran-5-ylmethyl)phenyl]-1-(hydroxymethyl)-6,8-dioxabicyclo[3.2.1]octane-2,3,4-triol Chemical compound C1=C2OCCC2=CC(CC=2C(Cl)=CC=C(C=2)[C@]23OC[C@](O2)([C@H]([C@H](O)[C@H]3O)O)CO)=C1 CBFXWKNXMYIBMA-CUUWFGFTSA-N 0.000 description 4
• JNIQHTGDRLOCRB-LDLUFFTGSA-N (1s,2s,3s,4r,5s)-5-[4-chloro-3-[[3-fluoro-4-(trideuteriomethoxy)phenyl]methyl]phenyl]-1-(hydroxymethyl)-6,8-dioxabicyclo[3.2.1]octane-2,3,4-triol Chemical compound C1=C(F)C(OC([2H])([2H])[2H])=CC=C1CC1=CC([C@@]23O[C@@](CO)(CO2)[C@@H](O)[C@H](O)[C@H]3O)=CC=C1Cl JNIQHTGDRLOCRB-LDLUFFTGSA-N 0.000 description 4
• CFAHXDCMZVZTKY-OTVISBKVSA-N (1s,2s,3s,4r,5s)-5-[4-chloro-3-[[4-(2,2,2-trifluoroethoxy)phenyl]methyl]phenyl]-1-(hydroxymethyl)-6,8-dioxabicyclo[3.2.1]octane-2,3,4-triol Chemical compound C=1C([C@]23OC[C@](O2)([C@H]([C@H](O)[C@H]3O)O)CO)=CC=C(Cl)C=1CC1=CC=C(OCC(F)(F)F)C=C1 CFAHXDCMZVZTKY-OTVISBKVSA-N 0.000 description 4
• GNTVCUSNVVDFIF-CUUWFGFTSA-N (1s,2s,3s,4r,5s)-5-[4-chloro-3-[[4-(2,2-difluoroethoxy)phenyl]methyl]phenyl]-1-(hydroxymethyl)-6,8-dioxabicyclo[3.2.1]octane-2,3,4-triol Chemical compound C=1C([C@]23OC[C@](O2)([C@H]([C@H](O)[C@H]3O)O)CO)=CC=C(Cl)C=1CC1=CC=C(OCC(F)F)C=C1 GNTVCUSNVVDFIF-CUUWFGFTSA-N 0.000 description 4
• ARHSAZVNLCYXIR-KNJMJIDISA-N (1s,2s,3s,4r,5s)-5-[4-chloro-3-[[4-(trifluoromethoxy)phenyl]methyl]phenyl]-1-(hydroxymethyl)-6,8-dioxabicyclo[3.2.1]octane-2,3,4-triol Chemical compound C=1C([C@]23OC[C@](O2)([C@H]([C@H](O)[C@H]3O)O)CO)=CC=C(Cl)C=1CC1=CC=C(OC(F)(F)F)C=C1 ARHSAZVNLCYXIR-KNJMJIDISA-N 0.000 description 4
• BTRYMXMKDSWQEU-UHFFFAOYSA-N (5-bromo-2-chlorophenyl)-(4-ethoxy-3-fluorophenyl)methanone Chemical compound C1=C(F)C(OCC)=CC=C1C(=O)C1=CC(Br)=CC=C1Cl BTRYMXMKDSWQEU-UHFFFAOYSA-N 0.000 description 4
• GGQCXRHQDDSHAE-UHFFFAOYSA-N 4-[(5-bromo-2-chlorophenyl)methyl]-2-fluorophenol Chemical compound C1=C(F)C(O)=CC=C1CC1=CC(Br)=CC=C1Cl GGQCXRHQDDSHAE-UHFFFAOYSA-N 0.000 description 4
• ABWOXAUTADIJBN-UHFFFAOYSA-N 4-bromo-1-chloro-2-[(4-ethoxy-3-fluorophenyl)methyl]benzene Chemical compound C1=C(F)C(OCC)=CC=C1CC1=CC(Br)=CC=C1Cl ABWOXAUTADIJBN-UHFFFAOYSA-N 0.000 description 4
• XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 4
• IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 4
• MHAJPDPJQMAIIY-UHFFFAOYSA-N Hydrogen peroxide Chemical compound OO MHAJPDPJQMAIIY-UHFFFAOYSA-N 0.000 description 4
• BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 4
• VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 4
• UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 description 4
• VSCWAEJMTAWNJL-UHFFFAOYSA-K aluminium trichloride Chemical compound Cl[Al](Cl)Cl VSCWAEJMTAWNJL-UHFFFAOYSA-K 0.000 description 4
• 239000012298 atmosphere Substances 0.000 description 4
• 229910052799 carbon Inorganic materials 0.000 description 4
• 150000001732 carboxylic acid derivatives Chemical class 0.000 description 4
• 239000003795 chemical substances by application Substances 0.000 description 4
• 239000000460 chlorine Substances 0.000 description 4
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